The goals of the Human Genome Project include the sequencing of the genome and the identification and characterization of human genes. To date, the characterization of human genes has mainly relied upon the sequencing of cDNA clones from libraries and the elucidation of possible function from homology searches against well characterized genes (usually from other organisms). In order to rapidly identify and characterize human genes involved in DNA repair and chromosome metabolism, we developed a new approach for the isolation of human genes that may play a role in these processes. This approach is based upon the idea that some human genes expressed in the yeast Saccharomyces cerevisiae can have dominant-negative effects on specific genetic endpoints and the function of such genes may relate to genetic endpoints in humans. Our initial experiments had demonstrated the potential for subcategorizing expressed human brain cDNAs according to effects on various genetic endpoints using yeast and we showed that a rad52 mutant (it sensitizes yeast to perturbations of its genome) could be used to isolate human genes that may function in DNA metabolism. Subsequent experiments revealed difficulties with the strains, so we have developed strains and additional test systems that can identify the relevant human genes. We are testing both the brain library and our newly developed inducible library from human testes in our new strains and in our sensitive genetic systems that can detect human genes which when overexpressed can affect DNA replication, chromosome stability, damage inducible signals, recombination of diverged DNAs (a model of many human genetic instabilities) and genes involved in the repair of UV and ionizing radiation DNA damage. We have also developed a screen for the detection of human cDNAs and yeast homologues that when expressed result in the induction of the SOS pathway in E. coli.